Terminal airway occlusion by hypersecretive mucus is a major manifestation in chronic obstructive pulmonary disease (COPD). In the cystic fibrosis lung, a genotype of COPD, hyperactive ENaC has already been proved to be a fundamental mechanism for dehydration of airway, in turn, causes impaired mucociliary clearance. However, little is known about the expression and regulation of ENaC channels in human COPD lung. The balance between protease and antiprotease in the airway mucus is crucial. It has been confirmed that reduction of the activity of 11-antitrypsin, a very important antiprotease inhibitor to inhibit elastase, an emphysema-causing enzyme released by neutrophils. Based on our previous and new exciting preliminary results, we hypothesize that ENaC expression is up-regulated in distal bronchoalveolar epithelial cells mediated by a protease-antiprotease imbalance in COPD lungs. Our two Specific Aims include: 1) to quantitatively investigate the expression patterns and subcellular locations of four ENaC subunits (1, 2, 3, and 4 ENaC) in the lung specimens collected from COPD;2) to investigate the expression levels and enzymatic activities of protease/antiprotease and their interactions with ENaC in the lung tissues in COPD. Results of these studies may provide a proof-of-concept for the correlation of ENaC expression, lung function, and clinicopathology in human COPD and discover dehydration of airway surface fluid as a novel target for developing new therapeutic strategies to combat COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is characterized by terminal airway occlusion. Over expression of a salt transport, namely, ENaC in mice results in COPD-like lung. Importantly, inhibition of ENaC will significantly improve their lung function. However, ENaC expression in human COPD lung has not been studied. We will examine ENaC subunit expression and their association with clinical severity. Our results will definitely provide answers to the question if ENaC is over expressed or not in human COPD lung. (End of Abstract)